Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis

Shimba, Shigeki; Ishii, Norimasa; Ohta, Yuki; Ohno, Toshiharu; Watabe, Yuichi; Hayashi, Mitsunori; Wada, Taira; Aoyagi, Toshinori; Tezuka, Masakatsu

doi:10.1073/pnas.0502383102

Cited by 478 publications

(368 citation statements)

References 41 publications

(44 reference statements)

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“…The first direct evidence that adipocytes posses the molecular machinery for a biological clock came from analysis in mice. 20 In 2005, Ando et al 14 demonstrated that the intracellular clock gene system acts in visceral AT and can be influenced by obesity or type 2 diabetes. Recently, it has been documented that these clock genes are expressed in AT from big mammals, specifically horse.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of BMAL1 in murine 3T3-L1 adipocytes not only induced the expression of several lipid metabolism-related factors, promoting lipogenesis, but also luciferase activity driven by the promoter of Per2, which is a known target gene of BMAL1, was increased. 20,31 A failure in the relationship between both clock genes, highly implicated in adipogenesis, could be influencing body fat distribution and the physiological disturbances related to abdominal fat accumulation. In the present moment, an increasing number of evidences point out that the disruption of the circadian system may have profound clinical relevance in some pathologies, including cancer disease and metabolic syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…37 Indeed, in the present work, clock genes expression in the subcutaneous fat was associated to total and LDL cholesterol, suggesting that in these morbid obese patients, the different clock genes are related to the disturbances associated to obesity. Shimba et al 20 recently showed that Bmal1 overexpression induces the transcription of lipogenic enzymes in 3T3-L1 adipocytes and the circadian expression of sterol regulatory element binding protein, which is highly implicated in cholesterol metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Clock genes are implicated in the human metabolic syndrome

et al. 2007

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Background: Clock genes play a role in adipose tissue (AT) in animal experimental models. However, it remains to be elucidated whether these genes are expressed in human AT. Objective: We investigated the expression of several clock genes, Bmal1, Per2 and Cry1, in human AT from visceral and subcutaneous abdominal depots. A second objective was to elucidate whether these clock genes expressions were related to the metabolic syndrome features. Methods: Visceral and subcutaneous AT samples were obtained from morbid obese men (n ¼ 8), age: 42713 years and body mass indexX40 kg/m 2 , undergoing laparoscopic surgery due to obesity. Biopsies were taken as paired samples at the beginning of the surgical process (1100 hour). Metabolic syndrome features such as waist circumference, plasma glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein (LDL) cholesterol were also studied. Homeostasis model assessment index of insulin resistance was also calculated. The expression of the different clock genes, hBmal1, hPer2 and hCry1, was determined by quantitative real-time PCR. Results: Clock genes were expressed in both human AT depots. hBmal1 expression was significantly lower than hPer2 and hCry1 in both AT (Po0.001). All genes were highly correlated to one another in the subcutaneous fat, while no correlation was found between Bmal1 and Per2 in the visceral AT. Clock genes AT expression was associated with the metabolic syndrome parameters: hPer2 expression level from visceral depot was inversely correlated to waist circumference (Po0.01), while the three clock genes studied were significantly and negatively correlated to total cholesterol and LDL cholesterol (Po0.01). Conclusion: We have demonstrated for the first time in humans that clock genes are expressed in both subcutaneous and visceral fat. Their association with abdominal fat content and cardiovascular risk factors may be an indicator of the potential role of these clock genes in the metabolic syndrome disturbances.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clock genes are implicated in the human metabolic syndrome

et al. 2007

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“…The Bmal1 gene, down-regulated in HF, is a transcription factor playing a central role in the regulation of circadian rhythms and seems to contribute to the regulation of adipogenesis and adipocyte functions (Shimba et al 2005). The Nr1d2 gene, up-regulated in HF, is highly expressed during daylight and represses Bmal1 transcription (Guillaumond et al 2005).…”

Section: Gene Expressionmentioning

confidence: 99%

The nutrigenomic investigation of C57BL/6N mice fed a short-term high-fat diet highlights early changes in clock genes expression

et al. 2013

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Mice fed long-term high-fat diets (HFD) are an established model for human metabolic disorders, such as obesity and diabetes. However, also the effects of shortterm HFD feeding should be investigated to understand which are the first events that trigger the onset of a predisease condition, the so-called metabolic syndrome, that increases the risk of developing clinical diseases. In this study, C57BL/6N mice were fed a control diet (CTR) or a HFD for 1 (T1) or 2 weeks (T2). Metabolic and histological effects were examined. Cecum transcriptomes of HFD and CTR mice were compared at T2 by microarray analysis. Differentially expressed genes were validated by real-time PCR in the cecum and in the liver. After 2 weeks of diet administration, HFD mice showed an altered expression pattern in only seven genes, four of which are involved in the circadian clock regulatory pathway. Real-time PCR confirmed microarray results of the cecum and revealed the same trend of clock gene expression changes in the liver. These findings suggest that clock genes may play an important role in early controlling gut output systems in response to HFD in mice and that their expression change may also represent an early signaling of the development of an intestinal pro-inflammatory status.

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“…Together, this core circadian regulatory complex constitutes a self-contained feedback loop whose rate-limiting protein levels oscillate in a ∼24-h manner. It is noteworthy that BMAL1, nocturnin, and Rev-erb α have all been implicated as transcriptional regulators of adipogenesis in pre-adipocyte cell models (Shimba et al 2004(Shimba et al , 2005Kawai et al 2010;Kumar et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Biological aging alters circadian mechanisms in murine adipose tissue depots

Sutton

Ptitsyn

Floyd

et al. 2012

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Biological aging alters the metabolism and volume of adipose tissue depots. Recent evidence suggests that circadian mechanisms play a role in promoting adipogenesis, obesity, and lipodystrophy.The current study compared cohorts of younger (5-9 months) and older (24-28 months) C57BL/6 mice as a function of biological age and circadian time. Advanced age significantly reduced the weight of the AGE (2013) 35:533-547 DOI 10.1007 Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9389-7) contains supplementary material, which is available to authorized users. brown, epididymal, inguinal, and retroperitoneal adipose depots but not total body weight. The older mice reduced their physical activity by >50% and delayed their activity initiation after light offset. The expressed transcriptome in brown and white adipose depots and liver of both cohorts displayed evidence of circadian rhythmicity; however, the oscillating mRNAs differed significantly between age groups and across tissues. The amplitude of Cry1, a component of the negative arm of the circadian apparatus, and downstream regulators such as Rev-erbα were elevated in the older relative to the younger cohorts as a function of circadian time. Overall, transcript levels differed significantly for 557 (inguinal adipose), 1,016 (liver), and 1,021 (brown adipose) expressed sequences between the cohorts as a function of age. These included transcripts encoding proteins within the canonical and non-canonical Wnt pathways. Since the Wnt pathway regulates adipose stem cell differentiation and shares a critical enzyme, glycogen synthase kinase 3β, with the circadian mechanism, the intersection between these two fundamental regulatory mechanisms merits further investigation with respect to biological aging of adipose tissues.

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Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis

Cited by 478 publications

References 41 publications

Clock genes are implicated in the human metabolic syndrome

Clock genes are implicated in the human metabolic syndrome

The nutrigenomic investigation of C57BL/6N mice fed a short-term high-fat diet highlights early changes in clock genes expression

Biological aging alters circadian mechanisms in murine adipose tissue depots

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